{"doi":"10.1128/spectrum.03729-25","title":"Dual human lung models reveal compartment-specific activity of anti-tuberculosis drugs and host-directed therapies","abstract":"<jats:title>ABSTRACT</jats:title>\n                  <jats:sec>\n                    <jats:title/>\n                    <jats:p>\n                      Tuberculosis (TB) remains a major global health challenge that requires new therapeutic strategies to improve drug efficacy, shorten treatment duration, prevent drug resistance, and limit\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis</jats:italic>\n                      (Mtb) persistence. Here, we established complementary\n                      <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                      human lung models integrating alveolar macrophage-like (AML) cells and airway air–liquid interface (ALI) cultures to evaluate standard-of-care antibiotics, host-directed therapies, and virulence-targeting agents. AMLs recapitulated key morphological, transcriptional, and functional features of primary alveolar macrophages, including a CD16\n                      <jats:sup>+</jats:sup>\n                      immunoregulatory phenotype highly permissive to Mtb infection. In parallel, ALI cultures maintained epithelial barrier integrity and secretory functions, allowing apical Mtb infection, drug penetration analysis, and inflammatory profiling. Benchmarking of standard-of-care antibiotics revealed compartment-specific activity: isoniazid, rifampicin, and moxifloxacin were effective in both systems, while pyrazinamide was active only in AMLs. Anti-inflammatory host-directed therapies, such as ibuprofen and doramapimod, selectively reduced cytokine production without affecting bacterial load. Together, this dual-platform system offers a physiologically relevant and scalable model to assess antimicrobial efficacy and host modulation across distinct pulmonary niches, bridging the gap between conventional macrophage assays and the complex human lung.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE</jats:title>\n                    <jats:p>\n                      Tuberculosis remains one of the world's deadliest infectious diseases. The development of new therapies is limited by the absence of human-relevant models that reproduce the distinct lung niches encountered by\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis</jats:italic>\n                      . Current macrophage or epithelial monocultures fail to predict how drugs act in the alveolar versus airway compartments, where intracellular and extracellular bacteria coexist and trigger different immune responses. Here, we introduce a dual human lung platform integrating alveolar macrophage-like cells and air–liquid interface airway epithelium. These models recapitulate key physiological features, including macrophage immunoregulatory programming, epithelial barrier function, mucociliary activity, and compartment-specific drug penetration. Benchmarking standard antibiotics, host-directed therapies, and antivirulence strategies revealed striking niche-dependent differences in antimicrobial and immunomodulatory activities. This system provides a powerful and accessible preclinical tool to evaluate antimicrobial and host-directed interventions in relevant human lung environments, helping bridge the gap between simplified\n                      <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                      assays and the complex biology of human tuberculosis.\n                    </jats:p>\n                  </jats:sec>","journal":"Microbiology Spectrum","year":2026,"id":652676,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1702666,"name":"Natacha Faivre","orcid":"0009-0008-0330-5519","position":1,"is_corresponding":false},{"id":1702667,"name":"Thomas Benoist","orcid":"0000-0003-0116-2629","position":2,"is_corresponding":false},{"id":1702668,"name":"Manon Popis","orcid":null,"position":3,"is_corresponding":false},{"id":1702670,"name":"Bastien Suire","orcid":null,"position":4,"is_corresponding":false},{"id":1702671,"name":"David Pericat","orcid":null,"position":5,"is_corresponding":false},{"id":1286676,"name":"José Manuel Sánchez-López","orcid":"0000-0002-1349-4746","position":6,"is_corresponding":false},{"id":1702674,"name":"Beatriz Melissa Aponte-Castillo","orcid":"0009-0004-5613-4718","position":7,"is_corresponding":false},{"id":1702676,"name":"Emmanuelle Näser","orcid":null,"position":8,"is_corresponding":false},{"id":1702678,"name":"Pénélope Viana","orcid":"0000-0003-0098-4831","position":9,"is_corresponding":false},{"id":1702679,"name":"Nicolas Guibert","orcid":null,"position":10,"is_corresponding":false},{"id":1702681,"name":"Romain Vergé","orcid":null,"position":11,"is_corresponding":false},{"id":595038,"name":"Julien Mazières","orcid":"0000-0002-5921-7613","position":12,"is_corresponding":false},{"id":1383959,"name":"Arnaud Métais","orcid":"0000-0002-9538-0338","position":13,"is_corresponding":false},{"id":312199,"name":"Renaud Poincloux","orcid":"0000-0003-2884-1744","position":14,"is_corresponding":false},{"id":1383970,"name":"Brigitte Raynaud-Messina","orcid":"0009-0000-1512-0871","position":15,"is_corresponding":false},{"id":1702684,"name":"Fabrice Dumas","orcid":"0000-0002-9164-4527","position":16,"is_corresponding":false},{"id":312206,"name":"Olivier Neyrolles","orcid":"0000-0003-0047-5885","position":17,"is_corresponding":false},{"id":312207,"name":"Christel Vérollet","orcid":"0000-0002-1079-9085","position":18,"is_corresponding":false},{"id":618275,"name":"Étienne Meunier","orcid":"0000-0002-3651-4877","position":19,"is_corresponding":false},{"id":312208,"name":"Geanncarlo Lugo‐Villarino","orcid":"0000-0003-4620-8491","position":20,"is_corresponding":false},{"id":312197,"name":"Céline Cougoule","orcid":"0000-0002-6795-5448","position":21,"is_corresponding":false},{"id":401786,"name":"Caio César Barbosa Bomfim","orcid":"0000-0003-1998-9237","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Dual human lung models reveal compartment-specific activity of anti-tuberculosis drugs and host-directed therapies","abstract":"<jats:title>ABSTRACT</jats:title>\n                  <jats:sec>\n                    <jats:title/>\n                    <jats:p>\n                      Tuberculosis (TB) remains a major global health challenge that requires new therapeutic strategies to improve drug efficacy, shorten treatment duration, prevent drug resistance, and limit\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis</jats:italic>\n                      (Mtb) persistence. Here, we established complementary\n                      <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                      human lung models integrating alveolar macrophage-like (AML) cells and airway air–liquid interface (ALI) cultures to evaluate standard-of-care antibiotics, host-directed therapies, and virulence-targeting agents. AMLs recapitulated key morphological, transcriptional, and functional features of primary alveolar macrophages, including a CD16\n                      <jats:sup>+</jats:sup>\n                      immunoregulatory phenotype highly permissive to Mtb infection. In parallel, ALI cultures maintained epithelial barrier integrity and secretory functions, allowing apical Mtb infection, drug penetration analysis, and inflammatory profiling. Benchmarking of standard-of-care antibiotics revealed compartment-specific activity: isoniazid, rifampicin, and moxifloxacin were effective in both systems, while pyrazinamide was active only in AMLs. Anti-inflammatory host-directed therapies, such as ibuprofen and doramapimod, selectively reduced cytokine production without affecting bacterial load. Together, this dual-platform system offers a physiologically relevant and scalable model to assess antimicrobial efficacy and host modulation across distinct pulmonary niches, bridging the gap between conventional macrophage assays and the complex human lung.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE</jats:title>\n                    <jats:p>\n                      Tuberculosis remains one of the world's deadliest infectious diseases. The development of new therapies is limited by the absence of human-relevant models that reproduce the distinct lung niches encountered by\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis</jats:italic>\n                      . Current macrophage or epithelial monocultures fail to predict how drugs act in the alveolar versus airway compartments, where intracellular and extracellular bacteria coexist and trigger different immune responses. Here, we introduce a dual human lung platform integrating alveolar macrophage-like cells and air–liquid interface airway epithelium. These models recapitulate key physiological features, including macrophage immunoregulatory programming, epithelial barrier function, mucociliary activity, and compartment-specific drug penetration. Benchmarking standard antibiotics, host-directed therapies, and antivirulence strategies revealed striking niche-dependent differences in antimicrobial and immunomodulatory activities. This system provides a powerful and accessible preclinical tool to evaluate antimicrobial and host-directed interventions in relevant human lung environments, helping bridge the gap between simplified\n                      <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                      assays and the complex biology of human tuberculosis.\n                    </jats:p>\n                  </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"42112802","pmcid":"PMC13227965","openalex_id":"https://openalex.org/W4416119758","authors":[],"funders":[{"funder_name":"Bill and Melinda Gates Foundation","grant_id":"INV-046428","title":null},{"funder_name":"Sidaction","grant_id":"22-2-AEQ-13457-1","title":null},{"funder_name":"H2020 Health","grant_id":"101080462","title":null},{"funder_name":"Fondation pour la Recherche Médicale","grant_id":"EQU202303016313","title":null},{"funder_name":"Agence Nationale de Recherches sur le Sida et les Hépatites Virales","grant_id":"2022-ECTZ190463, 2022-ECTZ205302, 2023-ECTZ293306","title":null}],"total_grants":5,"fwci":0.0,"citation_percentile":0.00532913,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1128/spectrum.03729-25","host_type":"journal"},{"url":"https://doi.org/10.1128/spectrum.03729-25","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/spectrum.03729-25","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.11.10.685269","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/42112802","host_type":"repository"},{"url":"https://hal.science/hal-05379754","host_type":"repository"},{"url":"https://doaj.org/article/0b9f0cc5c0554eb8b114da645a370a99","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/11/11/2025.11.10.685269.full.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC13227965","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC13227965?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Tuberculosis Research and Epidemiology","Inhalation and Respiratory Drug Delivery","Asthma and respiratory diseases"],"mesh_terms":["Host-Directed Therapy","Antitubercular Agents","Cells, Cultured","Humans","Lung","Mycobacterium tuberculosis","Tuberculosis","Tuberculosis, Pulmonary","Macrophages, Alveolar"],"keywords":["Drug","Lung","Pyrazinamide","Cytokine","Antibiotics","Immune system","Moxifloxacin","Mycobacterium tuberculosis","Alveolar macrophages","Antimicrobial Efficacy","Host-directed Therapy","Air–liquid Interface Cultures"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"gen"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T16:30:29.075662Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}